EP3434272A1 - Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid - Google Patents

Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid Download PDF

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EP3434272A1
EP3434272A1 EP17305998.1A EP17305998A EP3434272A1 EP 3434272 A1 EP3434272 A1 EP 3434272A1 EP 17305998 A EP17305998 A EP 17305998A EP 3434272 A1 EP3434272 A1 EP 3434272A1
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EP
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Prior art keywords
palbociclib
benzo
day
dihydro
fluoropropyl
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EP17305998.1A
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German (de)
French (fr)
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Sanofi SA
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Sanofi SA
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Priority to EP17305998.1A priority Critical patent/EP3434272A1/en
Priority to DK18740615.2T priority patent/DK3658147T3/en
Priority to ES18740615T priority patent/ES2906279T3/en
Priority to MA49673A priority patent/MA49673B1/en
Priority to CN201880048755.5A priority patent/CN111107851B/en
Priority to AU2018308871A priority patent/AU2018308871A1/en
Priority to US16/634,089 priority patent/US11260057B2/en
Priority to SG11202000367RA priority patent/SG11202000367RA/en
Priority to PL18740615T priority patent/PL3658147T3/en
Priority to PT187406152T priority patent/PT3658147T/en
Priority to RU2020107416A priority patent/RU2764116C2/en
Priority to CA3070754A priority patent/CA3070754A1/en
Priority to LTEPPCT/EP2018/069901T priority patent/LT3658147T/en
Priority to HUE18740615A priority patent/HUE057271T2/en
Priority to RS20220068A priority patent/RS62837B1/en
Priority to SI201830528T priority patent/SI3658147T1/en
Priority to JP2020503737A priority patent/JP6741897B1/en
Priority to BR112020001398-6A priority patent/BR112020001398A2/en
Priority to EP18740615.2A priority patent/EP3658147B1/en
Priority to HRP20212030TT priority patent/HRP20212030T1/en
Priority to KR1020207002003A priority patent/KR20200031622A/en
Priority to PCT/EP2018/069901 priority patent/WO2019020559A1/en
Priority to MYPI2020000179A priority patent/MY195271A/en
Priority to IL272166A priority patent/IL272166B2/en
Priority to ARP180102058 priority patent/AR112284A1/en
Priority to UY0001037818A priority patent/UY37818A/en
Priority to TW107125442A priority patent/TWI768087B/en
Publication of EP3434272A1 publication Critical patent/EP3434272A1/en
Priority to ZA2020/00145A priority patent/ZA202000145B/en
Priority to PH12020500091A priority patent/PH12020500091A1/en
Priority to CONC2020/0000240A priority patent/CO2020000240A2/en
Priority to US17/579,187 priority patent/US20220362248A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the estrogen receptor ⁇ (ESR1) is expressed in the majority of breast tumors, enabling them to respond to the mitogenic actions of estrogens.
  • compound (1) 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid, hereafter designated as "compound (1)", is a selective estrogen receptor degrader (SERD) which has complete estrogen receptor antagonist properties and accelerates the proteasomal degradation of the estrogen receptor.
  • SESD selective estrogen receptor degrader
  • Palbociclib also known as 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(1-piperazinyl)pyridine-2-ylamino]pyrido[2,3-d]pyrimidin-7(8H)-one, is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6.
  • Palbociclib is marketed under the tradename Ibrance ® and is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer, in combination with an aromatase inhibitor, or in combination with fulvestrant in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinizing hormone-releasing hormone (LHRH) agonist.
  • LHRH luteinizing hormone-releasing hormone
  • compound (1) may exist not only in the form of a zwitterion (i.e. a globally neutral molecule having an acid group and a basic group), but also in the form of addition salts with acids or bases. Such addition salts may be used in the above combination.
  • a combination comprising compound (1), or a pharmaceutically acceptable salt thereof, with palbociclib.
  • the combination of compound (1), or a pharmaceutically acceptable salt thereof, with palbociclib shows therapeutic synergy.
  • a combination demonstrates therapeutic synergy if its therapeutic effect is superior compared to the cumulative effect of either active agent of the combination alone.
  • compound (1), or a pharmaceutically acceptable salt thereof, and palbociclib are administered by the oral route.
  • composition comprising compound (1), or a pharmaceutically acceptable salt thereof, and palbociclib, as well as at least one pharmaceutically acceptable excipient.
  • excipients are selected from the customary excipients which are known to a person skilled in the art. More particularly, the excipients are selected from those useful for oral administration in whatever form (liquid solution, dispersion or suspension, tablets, capsules or the like).
  • compound (1), or a pharmaceutically acceptable salt thereof, and palbociclib may be administered simultaneously, separately, or spaced out over a period of time (sequential administration). Therefore, the combination provided herein is not exclusively limited to the one which is obtained by physical association of the constituents in a single pharmaceutical composition, but also to those which allow a separate administration, which can be simultaneous or spaced out over time.
  • a pharmaceutical kit which comprises:
  • the compound (1) or pharmaceutically acceptable salt thereof, and palbociclib are advantageously present at effective doses, adapted considering the treated pathology and the condition of the patient to which it is administered.
  • the recommended starting dose for cancer treatment for adult patients is 125 mg once daily for 21 days followed by 7 days off treatment, along with dosing interruption and/or dose reductions based on individual safety and tolerability.
  • the cancer is a hormone dependent cancer.
  • the cancer is an estrogen receptor dependent cancer, particularly the cancer is an estrogen receptor ⁇ dependent cancer.
  • the cancer is resistant to anti-hormonal treatment.
  • the cancer is a cancer with wild type estrogen receptors.
  • the cancer is a cancer with deregulated function of estrogen receptors related to, but not limited to, at least one epigenetic and genetic alteration of estrogen receptors such us mutation, amplification, splice variant.
  • the cancer is a cancer with mutated estrogen receptors.
  • the mutations of estrogen receptors can include, but not limited to, new or known mutations such us Leu536Arg, Tyr537Ser, Tyr537Asn, Asp538Gly.
  • the cancer is an estrogen-sensitive cancer.
  • the cancer is breast cancer, more particularly an estrogen receptor positive breast cancer (ER ⁇ positive breast cancer), or a metastasis thereof, such as a cerebral metastasis.
  • ER ⁇ positive breast cancer estrogen receptor positive breast cancer
  • metastasis thereof such as a cerebral metastasis.
  • a method of treating the pathological conditions indicated above, particularly breast cancer comprising administering to a subject in need thereof a therapeutically effective amount of compound (1), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of palbociclib.
  • the subject is a human.
  • a combination comprising compound (1), or a pharmaceutically acceptable salt thereof, and palbociclib for the manufacture of a medicament useful in treating in treating the pathological conditions indicated above, particularly breast cancer.
  • an article of manufacture comprising:
  • liquid chromatography/mass spectra were obtained on a UPLC Acquity Waters instrument, light scattering detector Sedere and SQD Waters mass spectrometer using UV detection DAD 210 ⁇ I ⁇ 400 nm and column Acquity UPLC CSH C18 1.7 ⁇ m, dimension 2.1x30 mm, mobile phase H 2 O + 0,1% HCO 2 H / CH 3 CN + 0,1% HCO 2 H.
  • reaction mixture was stirred at 60°C for 1 hour. After cooling to room temperature, the reaction mixture was poured into a mixture of water (500 ml) and AcOEt (400ml). The organic phase was washed with brine, dried over MgSO 4 , filtered on celite and concentrated under reduced pressure.
  • the treated groups included compound (1) at 5 mg/kg alone, palbociclib at 100 mg/kg alone, and the combination of compound (1) and palbociclib at the same dose and regime.
  • Compound (1) was orally dosed twice a day (BID) and palbociclib was orally dosed once a day (QD) for 30 days.
  • Anti-tumor efficacy was evaluated by tumor volume measurement.
  • mice Female athymic nude mice were obtained from Harlan (Indianapolis, IN, USA). Animals were allowed to acclimate for at least four days before the study enrollment. Mice were 12 to 13 weeks old and weighed between 20.2 and 27.3 grams at the beginning of the treatments. These animals were housed under conditions outlined in the NIH Guide for Care and Use of Laboratory Animals in compliance with the USDA Laboratory Animal Welfare Act.
  • MCF7-Y537S (ESR1) cell line was MCF7 cells expressing the ER.Y537S variant that was generated by Sanofi Biology Discovery Group.
  • Y537S mutation was introduced in ESR1 construct (GenBank NM_000125.3) by site directed mutagenesis ( Toy W. et al., Cancer Discovery, 2017, 7, 277-287 ). The construct was transfected in MCF7 cells which were selected for their growth in absence of estradiol.
  • MCF-Y537S is an ESR1 mutation that confers estrogen-independent activity to ER ⁇ (Estrogen Receptor alpha) and contributes to endocrine resistant disease ( Robinson D.R.
  • the cells were grown in Eagle's Minimum Essential Medium (EMEM) supplemented with 10% fetal bovine serum (FBS), human Insulin, in 5% CO 2 at 37°C.
  • EMEM Eagle's Minimum Essential Medium
  • FBS fetal bovine serum
  • FBS human Insulin
  • the cells were harvested in 0.25% Trypsin EDTA and washed by Dulbecco's Phosphate Buffered Saline (DPBS) and re-suspended in DPBS with 50% matrigel (Becton Dickinson catalog No. 356234, lot No. 32277).
  • the cells (20 ⁇ 10 6 cells/per mouse) were subcutaneously (SC) implanted into the right flank of female nude mice.
  • the tumors were reserved as tumor stocks for fragment implantation.
  • the tumors were serially propagated through fragment tissue transplantation subcutaneously.
  • the fragment tumor tissues were subcutaneously implanted into the right flank of female nude mice. 50 mice were assigned in this experiment.
  • Compound (1) was prepared in Vehicle A, then Solutol HS15 (purchased from Sigma) was added to the final concentration 5%, and the solution was left under stirring for an hour for complete dissolution. After that, vehicle B was added. The final pH was 5.5.
  • Palbociclib was prepared in Vehicle A, then Solutol HS15 was added to the final concentration 5%, and the solution was left under stirring for an hour for complete dissolution. After that, vehicle B was added. The final pH was 5.5.
  • mice were pooled and randomly distributed to the treatment and control groups (10 mice per group), where median tumor volumes for each group ranged from 202.5 to 211.5 mm 3 .
  • Treatments of compound (1) and palbociclib were initiated on day 22.
  • Compound (1) was orally administered at 5 mg/kg BID (at least 5 hours apart) and palbociclib was orally administered at 100 mg/kg QD, for 30 days. Animal body weight was assessed daily.
  • Examples include animal handling issues such as misgavage, tumor model related issues such as tumor induced cachexia leading to body weight loss that can be observed in control or vehicle treated groups and excessive tumor ulceration. Mice that have non-drug related death or significant bodyweight loss will not be considered toxic and will be excluded from statistical analysis. Animal body weight included the tumor weight.
  • the median percent regression for a group on a given day is then calculated by taking the median of individual % regression values calculated for each animal in the group.
  • the day of calculation is determined by the day when ⁇ T/ ⁇ C is calculated, excepted if median percent regression is not representative of the activity of the group. In this case, the day is determined by the first day when the median percent regression is maximal.
  • a two-way Anova-Type analysis with factors treatment and day (repeated) is performed on tumor volume changes from baseline. It is followed by contrast analyses with Bonferroni-Holm correction for multiplicity to compare all treated groups to the control group and to compare the combination versus each single agent at the dose involved in the combination at each day from day 27 to 51.
  • Tumor volume changes from baseline are calculated for each animal and each day by subtracting the tumor volume on the day of first treatment (day 21) from the tumor volume on the specified observation day.
  • Agent Route/ Dosage (in mL/kg per injection) Dosage in mg/kg per injection (total dose) Schedule in days (total of 30 days) *Unscheduled death (Day of death) Average body weight change in % per group at nadir (day of nadir) ⁇ T/ ⁇ C in % at day 51 Median % of regressions on day 51 Regressions p-value on day 47 # Biological Interpretation Partial Complete Vehicle PO, BID (10) - - 0/10 -2.2 (22) 100 - 0/10 0/10 - - Compound (1) PO, BID (10) 5 (295) N.B.
  • mice were excluded from statistical analysis because those mice corresponded to non-drug related death or terminations during the study.
  • Table 2 Efficacy of compound (1) combined with palbociclib against subcutaneous human breast cancer cell line MCF7-Y537S xenograft model in nude mice. Comparison of each group to the control group at each day.
  • nMAD Median Absolute Deviation
  • nMAD normalized MAD
  • nMAD 1.4826*MAD.
  • n number of animals. 3 mice were excluded from statistical analysis because those mice corresponded to non-drug related death or terminations during the study. Table 3: Efficacy of compound (1) combined with palbociclib against subcutaneous human breast cancer cell line MCF7-Y537S xenograft model in nude mice.
  • nMAD Median Absolute Deviation
  • nMAD normalized MAD
  • nMAD 1.4826*MAD
  • the effect of the combination of compound (1) at 5 mg/kg + palbociclib at 100 mg/kg is significantly greater than the effect of palbociclib at 100 mg/kg alone on day 34 to day 51.
  • the effect of the combination of compound (1) at 5 mg/kg + palbociclib at 100 mg/kg is significantly greater than the effect of compound (1) at 5 mg/kg alone on day 27 to day 51.
  • n number of animals. 3 mice were excluded from statistical analysis because those mice corresponded to non-drug related death or terminations during the study.

Abstract

Herein are provided a combination of palbociclib and of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid or a pharmaceutically acceptable salt thereof, a pharmaceutical composition containing such a combination, and the therapeutic uses thereof, in particular for the treatment of cancer, including breast cancer.

Description

  • Herein are provided a combination of palbociclib and of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid, a pharmaceutical composition containing such a combination, and the therapeutic uses of such combination and pharmaceutical composition, in particular for the treatment of cancer.
  • The estrogen receptor α (ESR1) is expressed in the majority of breast tumors, enabling them to respond to the mitogenic actions of estrogens.
  • 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid, hereafter designated as "compound (1)", is a selective estrogen receptor degrader (SERD) which has complete estrogen receptor antagonist properties and accelerates the proteasomal degradation of the estrogen receptor. This compound is disclosed in the patent application PCT/EP2017/053282 .
  • Palbociclib, also known as 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(1-piperazinyl)pyridine-2-ylamino]pyrido[2,3-d]pyrimidin-7(8H)-one, is an inhibitor of cyclin-dependent kinase (CDK) 4 and 6. Palbociclib is marketed under the tradename Ibrance® and is indicated for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer, in combination with an aromatase inhibitor, or in combination with fulvestrant in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinizing hormone-releasing hormone (LHRH) agonist.
  • There is always a need to find new antitumoral treatments. Now, it has been shown that a combination of compound (1) with palbociclib is well tolerated, demonstrates strong anti-tumor efficacy and induces tumor regression, with a synergistic effect compared to each of the active ingredient alone.
  • Herein is provided a combination comprising compound (1) with palbociclib.
  • In the combination provided herein, compound (1) may exist not only in the form of a zwitterion (i.e. a globally neutral molecule having an acid group and a basic group), but also in the form of addition salts with acids or bases. Such addition salts may be used in the above combination. Hence, herein is provided a combination comprising compound (1), or a pharmaceutically acceptable salt thereof, with palbociclib.
  • In an embodiment, the combination of compound (1), or a pharmaceutically acceptable salt thereof, with palbociclib shows therapeutic synergy. A combination demonstrates therapeutic synergy if its therapeutic effect is superior compared to the cumulative effect of either active agent of the combination alone.
  • In another embodiment, compound (1), or a pharmaceutically acceptable salt thereof, and palbociclib are administered by the oral route.
  • Provided herein is also a combination of compound (1), or a pharmaceutically acceptable salt thereof, and palbociclib for its use as a medicament.
  • Provided herein is also a pharmaceutical composition comprising compound (1), or a pharmaceutically acceptable salt thereof, and palbociclib, as well as at least one pharmaceutically acceptable excipient.
  • The excipients are selected from the customary excipients which are known to a person skilled in the art. More particularly, the excipients are selected from those useful for oral administration in whatever form (liquid solution, dispersion or suspension, tablets, capsules or the like).
  • In another embodiment, compound (1), or a pharmaceutically acceptable salt thereof, and palbociclib may be administered simultaneously, separately, or spaced out over a period of time (sequential administration). Therefore, the combination provided herein is not exclusively limited to the one which is obtained by physical association of the constituents in a single pharmaceutical composition, but also to those which allow a separate administration, which can be simultaneous or spaced out over time.
  • Herein is also provided a pharmaceutical kit which comprises:
    1. (i) a first pharmaceutical composition comprising compound (1), or a pharmaceutically acceptable salt thereof, as well as at least one pharmaceutically acceptable excipient;
    2. (ii) a second pharmaceutical composition comprising palbociclib, as well as at least one pharmaceutically acceptable excipient;
      both pharmaceutical compositions (i) and (ii) being in separate compartments and being intended to be independently administered, each administration with regards to the other one being simultaneous, separated or spread out over time.
  • In the pharmaceutical composition and pharmaceutical kit described above, the compound (1) or pharmaceutically acceptable salt thereof, and palbociclib are advantageously present at effective doses, adapted considering the treated pathology and the condition of the patient to which it is administered. In particular for palbociclib, the recommended starting dose for cancer treatment for adult patients is 125 mg once daily for 21 days followed by 7 days off treatment, along with dosing interruption and/or dose reductions based on individual safety and tolerability.
  • Herein is also provided a combination comprising compound (1), or a pharmaceutically acceptable salt thereof, with palbociclib, and to the pharmaceutical composition and kit defined above, for use in the treatment of cancer.
  • In another embodiment, the cancer is a hormone dependent cancer.
  • In another embodiment, the cancer is an estrogen receptor dependent cancer, particularly the cancer is an estrogen receptor α dependent cancer.
  • In another embodiment, the cancer is resistant to anti-hormonal treatment.
  • In another embodiment, the cancer is a cancer with wild type estrogen receptors.
  • In another embodiment, the cancer is a cancer with deregulated function of estrogen receptors related to, but not limited to, at least one epigenetic and genetic alteration of estrogen receptors such us mutation, amplification, splice variant.
  • In another embodiment, the cancer is a cancer with mutated estrogen receptors.
  • In another embodiment, the mutations of estrogen receptors can include, but not limited to, new or known mutations such us Leu536Arg, Tyr537Ser, Tyr537Asn, Asp538Gly.
  • In another embodiment, the cancer is an estrogen-sensitive cancer.
  • In another embodiment, the cancer is breast cancer, more particularly an estrogen receptor positive breast cancer (ERα positive breast cancer), or a metastasis thereof, such as a cerebral metastasis.
  • Herein is also provided a method of treating the pathological conditions indicated above, particularly breast cancer, comprising administering to a subject in need thereof a therapeutically effective amount of compound (1), or a pharmaceutically acceptable salt thereof, and a therapeutically effective amount of palbociclib. In an embodiment of this method of treatment, the subject is a human.
  • Herein is also provided a combination comprising compound (1), or a pharmaceutically acceptable salt thereof, and palbociclib for the manufacture of a medicament useful in treating in treating the pathological conditions indicated above, particularly breast cancer.
  • Herein is also provided an article of manufacture, a packaging, or an administration unit, comprising:
    • a packaging material;
    • the above defined combination, pharmaceutical composition or pharmaceutical kit; and
    • a label or package insert contained within said packaging material, indicating that said combination, pharmaceutical composition or pharmaceutical kit is administered to a patient for the treatment of cancer.
  • The examples below show how to synthesize compound (1), and the pharmacological results obtained with compound (1), palbociclib and their combination against a breast cancer cell line xenograft in mice.
    • 1 - Synthesis of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl) pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid
  • The experimental protocol for synthesizing 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid (compound (1)), described in the patent application PCT/EP2017/053282 , is reproduced below, along with its analytical data. The synthetic scheme for the synthesis of compound (1) is found in Figure 1.
  • The 1 H NMR spectra were performed on a Bruker Avance DRX-400 spectrometer, with the chemical shifts (δ in ppm) in the solvent dimethyl sulfoxide-d6 (d6-DMSO) referenced at 2.5 ppm at a temperature of 303 K. Coupling constants (J) are given in Hertz.
  • The liquid chromatography/mass spectra (LC/MS) were obtained on a UPLC Acquity Waters instrument, light scattering detector Sedere and SQD Waters mass spectrometer using UV detection DAD 210<I<400 nm and column Acquity UPLC CSH C18 1.7 µm, dimension 2.1x30 mm, mobile phase H2O + 0,1% HCO2H / CH3CN + 0,1% HCO2H.
  • The following abbreviations and empirical formulae are used:
    • AcOEt
    ethyl acetate
    AlCl3
    aluminium trichloride
    Cs2CO3
    cesium carbonate
    DCM
    dichloromethane
    DMF
    N,N-dimethylformamide
    DMSO
    dimethyl sulfoxide
    HCl
    hydrogen chloride
    K2CO3
    potassium carbonate
    LC/MS
    liquid chromatography/mass spectrometry
    MeOH
    methanol
    MgSO4
    magnesium sulfate
    NaHCO3
    sodium bicarbonate
    NaOH
    sodium hydroxyde
    Pd(dppf)Cl2
    1,1'bis(diphenylphosphino)ferrocene] dichloropalladium(II)
    Ph3P or P(Ph)3
    triphenylphosphine
    Ph3P=O
    triphenylphosphine oxide
    °C
    degrees Celsius
    ml
    millilitre(s)
    mmol
    millimole(s)
    µmol
    micromole(s)
    µM
    micromolar
    nM
    nanomolar
    ppm
    parts per million
    Intermediate (c). Tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenoxy]pyrrolidine-1-carboxylate
  • Figure imgb0001
     To a solution of commercially available 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (a) (82.7 g, 364.51 mmol) in THF (2 L) was added under argon (R)-1-N-Boc-3-hydroxypyrrolidine (b) (84.43 g, 437.41 mmol) followed by N,N,N',N'-tetramethylazodicarboxamide (99.1 g, 546.77 mmol). The clear reaction mixture turned orange and triphenylphosphine (143.41 g, 546.77 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours, meanwhile a precipitate of triphenylphosphine oxide formed (Ph3P=O). The reaction mixture was poured in water (1.5 L) and extracted with ethyl acetate (AcOEt) (3x1.5 L). Gathered organic phases were dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was taken up into diisopropylether (1.5 L) and the solid formed (Ph3P=O) was filtered. The solvent was concentrated under reduced pressure and the residue purified by column chromatography eluting with a mixture of heptane with AcOEt (90/10; v/v) to give 145 g (100%) of tert-butyl (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine-1-carboxylate (c) as a colorless oil.
    1H NMR (400 MHz, DMSO-d6, δ ppm): 1.27 (s : 12H); 1.39 (s : 9H); 2,05 (m : 1H); 2,14 (m : 1H); 3,37 (3H); 3,55 (m, : 1H); 5,05 (s : 1H); 6,94 (d , J = 8,4 Hz : 2H); 7,61 (d, J = 8,4 Hz : 2H)
    • Intermediate (d). (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenoxy]pyrrolidine, hydrochloride
  • Figure imgb0002
     To a solution of (S)-tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine-1-carboxylate (c) (80 g, 195.23 mmol) in MeOH (450 ml) was added slowly HCl 4N in dioxane (250 ml).
    After 1.5 hours, the reaction mixture was concentrated under reduced pressure and the residue was taken up into Et2O with stirring to give a solid which then was filtered and dried under vacuum to give 61.8 g (95%) of (3S)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenoxy]pyrrolidine, hydrochloride (d) as a white powder.
    1H NMR (400 MHz, DMSO-d6, δ ppm): 1.28 (s : 12H); 2,10 (m : 1 H) ; 2,21 (m : 1 H) ; 3,31 (3H); 3,48 (m, : 1H); 5,19 (m : 1H); 6,97 (d, J = 8,4 Hz : 2H); 7,63 (d, J = 8,4 Hz : 2H); 9,48 (s: 1 H) ; 9,71 (s: 1H).
    LC/MS (m/z, MH+): 290
    • Intermediate (e). (3S)-1-(3-fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine
  • Figure imgb0003
     To a suspension of (S)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyrrolidine hydrochloride (d) (20 g, 61.42 mmol) in acetonitrile (100 ml), was added K2CO3 (21.22 g, 153.54 mmol) and 1-iodo-3-fluoropropane (12.15 g, 61.42 mmol), under argon. The reaction mixture was stirred at 40°C for 24 hours. After cooling to room temperature, the reaction mixture was filtered and washed with acetonitrile. The filtrate was concentrated under reduced pressure and the residue was taken up in DCM and the solid formed was filtered and washed with DCM. The filtrate was concentrated to give 21.5 g (100%) of (3S)-1-(3-fluoropropyl)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (e) as a yellow foam.
    1H NMR (400 MHz, DMSO-d6, δ ppm): 1,27 (s : 12H); 1,77 (m : 2H) ; 1,84 (m : 1H) ; 2,27 (m : 1 H) ; 2,41 (m : 1 H) ; 2,49 (2H) ; 2,62 (dd, J = 2,6 and 10,4Hz : 1 H) ; 2,69 (m : 1 H) ; 2,83 (dd, J = 6,2 and 10,4Hz : 1 H) ; 4,47 (td, J = 6,2 and 47Hz : 2H) ; 4,99 (m : 1 H) ; 6,77 (d , J = 8,4 Hz : 2H); 7,58 (d , J = 8,4 Hz : 2H). LC/MS (m/z, MH+): 350
    • Intermediate (B). 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl 2,2-dimethylpropanoate
  • Figure imgb0004
     To a solution of 2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (A) (1.52 g, 8.63 mmol), in acetone (60 ml), was added K2CO3 (1.19 g, 8.63 mmol) and pivaloyl chloride (1.06 ml, 8.63 mmol). The reaction mixture was stirred at room temperature for 16 hours, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane in AcOEt (100/0 to 85/15, v/v) to give 1.55 g (69%) of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl 2,2-dimethylpropanoate (B) as a colorless oil.
    1H NMR (400 MHz, DMSO-d6, δ ppm): 7.65 (d, 1 H); 7.10-7.04 (m, 2H); 2.95 (t, 2H); 2.68 (t, 2H); 1.85-1.65 (m, 4H).
    LC/MS (m/z, MH+): 261
    • Intermediate (C). 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl 2,2-dimethylpropanoate
  • Figure imgb0005
     To a solution of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl 2,2-dimethylpropanoate (B) (15 g, 57.62 mmol) in DCM (500 ml) was added dropwise under argon pyridine (7.28 ml, 86.43 mmol) and trifluoromethanesulfonic anhydride (19.58 ml, 115.24 mmol). The reaction mixture was stirred at room temperature for 2 hours and ice (200 g) was added. The phases were separated, the aqueous phase was washed with DCM and the gathered organic phases were dried over MgSO4, filtered and evaporated under reduced pressure to give 22 g (97%) of 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl 2,2-dimethylpropanoate (C) as a white solid.
    LC/MS (m/z, MH-): 391
    • Intermediate (D). 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate
  • Figure imgb0006
     To a solution of 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (C) (22 g, 56.07 mmol) and (3S)-1-(3-fluoropropyl)-3-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (e) (20.56 g, 58.87 mmol) in dioxane (420 ml) and water (120 ml) was added under argon Pd(dppf)Cl2 (2.75 g, 3.36 mmol) and Cs2CO3 (36.57 g, 112.13 mmol). The reaction mixture was stirred for 1 hour at room temperature and was partitioned between water and DCM. The aqueous phase was washed with DCM and the gathered organic phases dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of MeOH in DCM (0 to 5%; V/V) to give 31 g (100 %) of 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (D).
    LC/MS (m/z, MH+): 466
    • Intermediate (E). 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol
  • Figure imgb0007
     To a solution under argon of 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl-2,2-dimethylpropanoate (D) (24.8 g, 53.26 mmol) in MeOH (300 ml), was added NaOH 5M (23 ml, 115.00 mmol). The reaction mixture was stirred for 2 hours at room temperature. pH was then adjusted to 7 by addition of 6N aqueous HCl solution. The MeOH was concentrated under reduced pressure, then DCM was added. The organic phase was dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/ MeOH from 100/0 to 95/05 to give 18.8 g (93%) of 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (E) as a beige solid.
    LC/MS (m/z, MH+): 382
    • Intermediate (F). 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate
  • Figure imgb0008
     To a solution of 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-ol (E) (20.6 g, 54.00 mmol) in DCM (200 ml) and pyridine (6.55 ml, 81.00 mmol), cooled to 5°C (ice bath), was added dropwise trifluoromethanesulfonic anhydride (18.93 ml, 108.00 mmol) under argon, and the reaction temperature was maintained <15°C. The ice bath was removed, and the brown suspension was stirred at room temperature for 2 hours. Ice (200 g) and DCM (200 ml) were added and the phases separated. The organic phase was dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/0 to 95/05 to give 24.7 g (89.1%) of 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate (F) as a brown oil.
    LC/MS (m/z, MH+):514
    • Intermediate (G). Methyl 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate
  • Figure imgb0009
     To a solution of 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulen-3-yl trifluoromethanesulfonate (F) (10.1 g, 19.67 mmol) in DMF (66 ml) and MeOH (33 ml), were added Pd(dppf)Cl2 (909 mg, 1.18 mmol) and diisopropylethylamine (7.21 ml). The black suspension was carbonylated in an autoclave at 70°C under 5 bars of CO for 5 hours. The reaction mixture was filtered, then the filtrate was partially concentrated under reduced pressure. The residue was partitioned between AcOEt and water. The organic phase was washed with water (2x 100 ml), dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/ MeOH from 100/0 to 95/05 to give 7.13 g (86%) of methyl 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (G) as a brown gum.
    LC/MS (m/z, MH+): 424
    • Intermediate (A1). 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yltrifluoromethanesulfonate
  • Figure imgb0010
     To a solution of commercially available 2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (A) (18.5 g, 105 mmol) in DCM (185 ml) and lutidine (13.35 ml, 113.505 mmol), cooled at 5°C under argon, was added dropwise trifluoromethanesulfonic anhydride (20.22 ml, 123.29 mmol) while keeping temperature between 10 and 20°C. The reaction mixture was stirred for 1 hour at 5°C then at room temperature for 1 hour.
    Then, ice (200 g) was added and the slurry partitioned between water and DCM. The organic phase was washed with aqueous NaHCO3 solution, dried over MgSO4, filtered off and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane/AcOEt from 100 to 90/10 to give 28.2 g (87%) of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate (A1) as an orange oil.
    LC/MS (m/z, MH+): 309
    • Intermediate (B1). Methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate
  • Figure imgb0011
     To a solution of 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate (A1) (5.03 g, 16.32 mmol) in DMF (24 ml) and MeOH (12 ml), were added Pd(dppf)Cl2 (754 mg, 0.98 mmol) and diisopropylethylamine (6 ml). The black suspension was carbonylated in an autoclave at 70°C under 5 bars of CO for 2.5 hours. The reaction mixture was filtered, then the filtrate was partially concentrated under reduced pressure, and the residue, was partitioned between AcOEt and water. The organic phase was washed with water (2x 75 ml) and aqueous HCl 0.5 N, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of heptane/AcOEt from 100/0 to 90/10 to give 3.4 g (95%) of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (B1) as a colorless oil.
    LC/MS (m/z, MH+): 219
    • Intermediate (C1). methyl 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate
  • Figure imgb0012
     To a solution of methyl 5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylate (B1) (18,19 g, 83,34 mmol) in DCM (500 ml) and anhydrous pyridine (11 ml, 130,56 mmol), cooled at 5°C under argon, was added dropwise trifluoromethanesulfonic anhydride (30 ml, 176,54 mmol). The reaction mixture, a thick suspension, was stirred at room temperature for 24 hours, then ice was added and partitioned between water and DCM. The organic phase was dried over MgSO4, filtered off and concentrated under reduced pressure to give 29 g (100%) of methyl 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (C1) as a yellow gum.
    LC/MS (m/z, MH+): 351
    • Intermediate (G). methyl 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate
  • Figure imgb0013
     To a solution of methyl 9-(trifluoromethanesulfonyloxy)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (C1) (29 g, 82.9 mmol), (3S)-1-(3-fluoropropyl)-3-[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]pyrrolidine (e) (28.9 g, 82.9 mmol), in dioxane (225 ml) were added Pd(dppf)Cl2 under argon, complex with DCM (3.73 g, 4.57 mmol) and Cs2CO3 1.5 M aqueous solution (111.12 ml, 166.68 mmol). The reaction mixture was stirred at 60°C for 1 hour.
    After cooling to room temperature, the reaction mixture was poured into a mixture of water (500 ml) and AcOEt (400ml). The organic phase was washed with brine, dried over MgSO4, filtered on celite and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/0 to 95/05 to give 23 g (65%) of methyl 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (G) as a brown gum.
    LC/MS (m/z, MH+): 424
    • Intermediate (H). Methyl 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide
  • Figure imgb0014
     To a solution of methyl 9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate (G) (13.93 g, 32.89 mmol), in DCM (150 ml) was added under argon pyridinium tribromide (15.78 g, 44.41 mmol). The reaction mixture was stirred for 1 hour at room temperature. Water (200 ml) was added, organic phase was then dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography eluting with a gradient of DCM/MeOH from 100/0 to 95/05 to give 16.4 g (85%) of methyl 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide (H) as a yellow meringue.
    LC/MS (m/z, MH+): 502
    • Intermediate (I). 6-(2,4-dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester.
  • Figure imgb0015
     To a solution of methyl 8-bromo-9-(4-{[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxy}phenyl)-6,7-dihydro-5H-benzo[7]annulene-3-carboxylate hydrobromide (H) (150 mg, 298.56 µmol), in dioxane (12 ml) and water (2 ml), was added 2,4-dichlorophenyl-boronic acid (62.67 mg, 328.41 µmol), Cs2CO3 (204.48 mg, 626.97 µmol), and Pd(dppf)Cl2 (14.63 mg, 17.91 µmol). The reaction mixture was heated at 90°C for 3 hours, and partitioned between AcOEt and water. The phases were separated and the organic phase washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (96/2/2; V/V/V) to give 80 mg (47%) of 6-(2,4-dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester (I).
    LC/MS (m/z, MH+): 568
    • Compound (1). 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid
  • Figure imgb0016
     To a solution of 6-(2,4-dichloro-phenyl)-5-{4-[1-(3-fluoro-propyl)-pyrrolidin-3-yloxy]-phenyl}-8,9-dihydro-7H-benzocycloheptene-2-arboxylic acid methyl ester (I) (80 mg, 140.72 µmol) in MeOH (5 ml) was added a solution of NaOH (562.88 µl, 5 M) and the reaction mixture was heated at 60°C for 5 hours and the solvent removed under reduced pressure. The residue was taken up in water (10 ml) and aqueous HCl (5 M) added to pH 7. The slurry was extracted with DCM, dried over MgSO4 and concentrated under reduced pressure. The solid was purified by column chromatography eluting with a mixture of DCM, acetonitrile and MeOH (90/5/5; V/V/V) to give 60 mg (77%) of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid.
    1 H NMR (400 MHz, DMSO-d6, δ ppm): 1,68 (m, 1 H) ; 1,79 (dm, J=25,3 Hz, 2 H); 2,07 to 2,23 (m, 5 H); 2,38 (m, 1 H) ; 2,46 (t, J=7,2 Hz, 2 H) ; 2,52 (m , 1 H) ; 2,62 (m, 1 H); 2,55 to 2,89 (m, 3 H); 4,47 (td, J=6,2 and 47,6 Hz, 2 H) ; 4,72 (m, 1 H) ; 6,63 (d , J=8,9 Hz, 2 H) ; 6,71 (m, 3 H); 7,18 (d, J=8,4 Hz, 1 H) ; 8,26 (dd, J=2,0 and 8,4 Hz, 1 H) ; 7,58 (d, J=2,0 Hz, 1 H) ; 7,63 (d , J=8,4 Hz, 1 H) ; 7,79 (s , 1 H) ; 12,3 (m, 1 H)
    LC/MS (m/z, MH+): 554
    • 2 - Evaluation of the efficacy of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl) pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid combined with palbociclib against a subcutaneous breast cancer cell line xenograft in female nude mice
  • In the present study, the anti-tumor efficacy of 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid ("compound (1)"), combined with the cyclin-dependent kinase 4 (CDK4) inhibitor palbociclib, was investigated after 30 days treatment against a subcutaneous MCF7-Y537S human breast cancer cell line xenograft in female nude mice.
  • The treated groups included compound (1) at 5 mg/kg alone, palbociclib at 100 mg/kg alone, and the combination of compound (1) and palbociclib at the same dose and regime.
  • Compound (1) was orally dosed twice a day (BID) and palbociclib was orally dosed once a day (QD) for 30 days. Anti-tumor efficacy was evaluated by tumor volume measurement.
    • 2-1: Experimental procedure 2-1-1: Animals, cell line, compounds
  • Female athymic nude mice were obtained from Harlan (Indianapolis, IN, USA). Animals were allowed to acclimate for at least four days before the study enrollment. Mice were 12 to 13 weeks old and weighed between 20.2 and 27.3 grams at the beginning of the treatments. These animals were housed under conditions outlined in the NIH Guide for Care and Use of Laboratory Animals in compliance with the USDA Laboratory Animal Welfare Act.
  • Parental MCF7 cells were obtained from the American Type Culture Collection (ATCC® HTB-22™). MCF7-Y537S (ESR1) cell line was MCF7 cells expressing the ER.Y537S variant that was generated by Sanofi Biology Discovery Group. Y537S mutation was introduced in ESR1 construct (GenBank NM_000125.3) by site directed mutagenesis (Toy W. et al., Cancer Discovery, 2017, 7, 277-287). The construct was transfected in MCF7 cells which were selected for their growth in absence of estradiol. MCF-Y537S is an ESR1 mutation that confers estrogen-independent activity to ERα (Estrogen Receptor alpha) and contributes to endocrine resistant disease (Robinson D.R. et al., Nat Genet., 2013, 45 (12), 1446-1451). The cells were grown in Eagle's Minimum Essential Medium (EMEM) supplemented with 10% fetal bovine serum (FBS), human Insulin, in 5% CO2 at 37°C. The cells were harvested in 0.25% Trypsin EDTA and washed by Dulbecco's Phosphate Buffered Saline (DPBS) and re-suspended in DPBS with 50% matrigel (Becton Dickinson catalog No. 356234, lot No. 32277). The cells (20 × 106 cells/per mouse) were subcutaneously (SC) implanted into the right flank of female nude mice.
  • When the MCF7-Y537S tumors were established, the tumors were reserved as tumor stocks for fragment implantation. The tumors were serially propagated through fragment tissue transplantation subcutaneously. The fragment tumor tissues were subcutaneously implanted into the right flank of female nude mice. 50 mice were assigned in this experiment.
  • Compound (1) and palbociclib (commercially available, marketed under the tradename Ibrance®) were formulated as follows:
    • Vehicle A: 20% Labrasol® (supplied from Gattefosse SAS, France);
    • Vehicle B: 5% Dextrose.
  • Compound (1) was prepared in Vehicle A, then Solutol HS15 (purchased from Sigma) was added to the final concentration 5%, and the solution was left under stirring for an hour for complete dissolution. After that, vehicle B was added. The final pH was 5.5.
    • Dose volume for compound (1) administration: 10 ml/kg by oral gavage.
    • Doses: 5 mg/kg (dosage of compound (1) in the above volume).
  • Palbociclib was prepared in Vehicle A, then Solutol HS15 was added to the final concentration 5%, and the solution was left under stirring for an hour for complete dissolution. After that, vehicle B was added. The final pH was 5.5.
    • Dose volume: 10 ml/kg by oral gavage.
    • Doses: 100 mg/kg (dosage of palbociclib in the above volume).
    2-1-2: Study design, end points
  • The animals required for experiment (plus extra) were pooled and implanted with MCF7-Y537S tumor fragment tissues on day 0. On day 21 post implantation, the mice were pooled and randomly distributed to the treatment and control groups (10 mice per group), where median tumor volumes for each group ranged from 202.5 to 211.5 mm3. Treatments of compound (1) and palbociclib were initiated on day 22. Compound (1) was orally administered at 5 mg/kg BID (at least 5 hours apart) and palbociclib was orally administered at 100 mg/kg QD, for 30 days. Animal body weight was assessed daily.
  • The dosages are expressed in mg/kg and based on daily body weight per animal. Vehicle treated animals were used as controls. Mice were checked daily and adverse clinical reactions noted. Individual mice were weighed daily until the end of the experiment. Mice would be euthanized when morbid or weight loss ≥20% was observed. Tumors were measured with a caliper twice weekly until final sacrifice. When a tumor size reached approximately 2000 mm3 or when there are animal health issues (40% area of a tumor ulcerated), animals would be euthanized and date of death recorded. Solid tumor volumes were estimated from two dimensional tumor measurements and calculated according to the following equation: Tumor volume mm 3 = length mm × width 2 mm 2 2
    Figure imgb0017
    • Toxicity end points:
  • A dosage producing either 15% body weight loss during 3 consecutive days for an individual mouse, 20% body weight loss during 1 day, or 10% or more drug related deaths, was considered an excessively toxic dosage, unless under certain circumstances bodyweight loss or animal death can be considered non-drug related. Examples include animal handling issues such as misgavage, tumor model related issues such as tumor induced cachexia leading to body weight loss that can be observed in control or vehicle treated groups and excessive tumor ulceration. Mice that have non-drug related death or significant bodyweight loss will not be considered toxic and will be excluded from statistical analysis. Animal body weight included the tumor weight.
    • Efficacy end points:
  • The primary efficacy end points include tumor volume changes from baseline summarized by the ratio of medians of tumor volume changes from baseline between the treated and control groups (ΔT/ΔC). Changes in tumor volume for each treated (T) and control (C) group are calculated for each animal on each day by subtracting the tumor volume on the day of first treatment (staging day) from the tumor volume on the specified observation day. The median ΔT is calculated for the treated group and the median ΔC is calculated for the control group. The ratio ΔT/ΔC is calculated and expressed as percentage: Δ T / Δ C = Median deltatT Median deltaC × 100
    Figure imgb0018
  • ΔT/ΔC ≤ 40% is considered as therapeutically active, ΔT/ΔC = 0% is considered as tumor stasis, and ΔT/ΔC < 0% is considered as tumor regression (very active). ΔT/ΔC > 40% is considered as therapeutically inactive.
  • Percent tumor regression is defined as % (percentage) of tumor volume decrease in the treated group on a specified observation day compared to its volume when the study was initiated. At a specific time point (t) and for each animal, the regression percentage is calculated using the following formula: % regression at t = volume t 0 − volume t volume t 0 × 100
    Figure imgb0019
  • The median percent regression for a group on a given day is then calculated by taking the median of individual % regression values calculated for each animal in the group. The day of calculation is determined by the day when ΔT/ΔC is calculated, excepted if median percent regression is not representative of the activity of the group. In this case, the day is determined by the first day when the median percent regression is maximal.
    • 2-1-3: Statistical analysis
  • A two-way Anova-Type analysis with factors treatment and day (repeated) is performed on tumor volume changes from baseline. It is followed by contrast analyses with Bonferroni-Holm correction for multiplicity to compare all treated groups to the control group and to compare the combination versus each single agent at the dose involved in the combination at each day from day 27 to 51.
  • In the figures, the medians and Median Absolute Deviation (MAD) of each group are represented for each day of measurement.
  • In the tables, the medians and Normalized MAD (nMAD = 1.4826*MAD) of each group are reported for each day of measurement.
  • Tumor volume changes from baseline are calculated for each animal and each day by subtracting the tumor volume on the day of first treatment (day 21) from the tumor volume on the specified observation day.
  • All statistical analyses were performed using SAS version 9.2 software. A probability of less than 5% (p<0.05) was considered as significant.
    • 2-2: Results
  • Compound (1) at 5 mg/kg BID, palbociclib 100 mg/kg QD and the combination of compound (1) and palbociclib at the doses and regime for 30 days were well tolerated in this study showing average body weight change in % per group at nadir (the lowest of body weight drop in the group) of -1.7% (day 22), -2.0% (day 22) and -6.4% (day 26), respectively (Table 1).
  • Compound (1) at a dose of 5 mg/kg BID for 30 days had minimal effect on tumor growth with ΔT/ΔC value of 59% (p = 0.4113) on day 51. Palbociclib at a dose of 100 mg/kg QD for 30 days achieved anti-tumor efficacy with ΔT/ΔC value of 27% (p<0.0001) on day 51. When compound (1) at 5 mg/kg combined with palbociclib 100 mg/kg with the same dose regime as BID for compound (1) and QD for palbociclib, the combination treatment demonstrated strong anti-tumor efficacy with ΔT/ΔC value less than 0 (p < 0.0001) and induced tumor regression (median tumor regression 32%) on day 51. The statistical analysis indicated the combination effect was significantly different when compared to either compound (1) alone or palbociclib alone on day 51 (p <0.0001). Detailed results are shown in Tables 1, 2 and 3 below, as well as in Figures 2 and 3:
    • Figure 2: Antitumor activity of compound (1) combined with palbociclib against subcutaneous human breast cancer cell line MCF7-Y537S xenograft in nude mice: tumor volume evolution. The curves represent medians + or- MAD (Median Absolute Deviation) at each day for each group;
    • Figure 3: Antitumor activity of compound (1) combined with palbociclib against subcutaneous human breast cancer cell line MCF7-Y537S xenograft in nude mice: tumor volume changes from baseline on day 51. Points represent individual tumor volume changes from baseline on day 51, bars correspond to medians.
  • From this experiment, we conclude that the compound (1) at 5 mg/kg twice a day combined with the CDK4 inhibitor palbociclib at 100 mg/kg once a day induced significant anti-tumor efficacy and tumor regression in MCF7-Y537S human breast cancer cell line xenograft model in nude mice that was superior to single agents alone. Table 1: Efficacy of compound (1) combined with palbociclib against subcutaneous MCF7-Y537S human breast cancer xenograft in nude mice.
    Agent Route/ Dosage (in mL/kg per injection) Dosage in mg/kg per injection (total dose) Schedule in days (total of 30 days) *Unscheduled death (Day of death) Average body weight change in % per group at nadir (day of nadir) ΔT/ΔC in % at day 51 Median % of regressions on day 51 Regressions p-value on day 47# Biological Interpretation
    Partial Complete
    Vehicle PO, BID (10) - - 0/10 -2.2 (22) 100 - 0/10 0/10 - -
    Compound (1) PO, BID (10) 5 (295) N.B. 22 to 51 2/10 -1.7 (22) 59 NR 0/8 0/8 p = 0.4113 Inactive
    Palbociclib PO, QD (10) 100 (3000) 22 to 51 0/10 -2.0 (22) 27 NR 0/10 0/10 p < 0.0001 Active
    Compound (1) + Palbociclib PO, BID (10) 5 (295) N.B. + 100 (3000) 22 to 51 1/10 -2.3 (26) <0 32 2/9 0/9 p < 0.0001 Very active
    PO, QD (10)
    PO: per os
    N.B.: animals accepted one dose in the starting date.
    NR: no regression (0% regression).
    # Statistical analysis: Comparison of each single agent and combination versus the control group. The p-values were obtained using a contrast analysis to compare each treated group versus control at each day using Bonferroni-Holm adjustment for multiplicity after a two-way Anova-Type with repeated measures on tumor volume changes from baseline. A probability less than 5% (p<0.05) was considered as significant.
    *3 mice were excluded from statistical analysis because those mice corresponded to non-drug related death or terminations during the study.
    Table 2: Efficacy of compound (1) combined with palbociclib against subcutaneous human breast cancer cell line MCF7-Y537S xenograft model in nude mice. Comparison of each group to the control group at each day.
    Tumor volume changes from baseline mm3: Median (nMAD)*, n and p-value#
    Treatment Group Global Day 27 Day 30 Day 34 Day 37 Day 41 Day 44 Day 49 Day 51
    Control - 111.5 (44.48) n=10 181.0 (78.58) n=10 296.0 (133.43) n=10 392.0 (235.73) n=10 663.0 (363.24) n=10 867.0 (456.64) n=10 1140.0 (615.28) n=10 1322.0 (633.07) n=10
    Compound (1) 5 mg/kg - 114.0 (19.27) n=8 171.5 (31.13) n=8 270.5 (112.68) n=8 336.0 (112.68) n=8 440.0 (39.29) n=8 498.5 (91.18) n=8 727.5 (160.86) n=8 782.0 (112.68) n=8
    0.3975 0.6333 0.3909 0.7343 0.5990 0.2495 0.1950 0.3770 0.4113
    Palbociclib 100 mg/kg - 68.5 (31.88) n=10 98.0 (25.20) n=10 121.5 (34.10) n=10 132.0 (31.88) n=10 193.5 (52.63) n=10 249.5 (43.74) n=10 298.5 (97.11) n=10 363.5 (108.23) n=10
    <0.0001 0.1164 0.0009 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001
    Compound (1) 5 mg/kg + Palbociclib 100 mg/kg - -8.0 (63.75) n=9 -17.0 (97.85) n=9 -35.0 (74.13) n=9 -30.0 (57.82) n=9 -43.0 (60.79) n=9 -63.0 (45.96) n=9 -53.0 (72.65) n=9 -52.0 (72.65) n=9
    <0.0001 0.0077 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001
    # p-values obtained with a contrast analysis versus control at each day with Bonferroni-Holm adjustment for multiplicity after a two-way Anova-Type on tumor volume changes from baseline.
    * MAD= Median Absolute Deviation; nMAD= normalized MAD; nMAD= 1.4826*MAD.
    For palbociclib at 100 mg/kg, the effect on tumor volume changes from baseline is significant compared to the control group from day 30 to day 51.
    For the combination compound (1) at 5 mg/kg + palbociclib at 100 mg/kg, the effect on tumor volume changes from baseline is significant compared to the control group from day 27 to day 51.
    n = number of animals. 3 mice were excluded from statistical analysis because those mice corresponded to non-drug related death or terminations during the study.
    Table 3: Efficacy of compound (1) combined with palbociclib against subcutaneous human breast cancer cell line MCF7-Y537S xenograft model in nude mice. Comparison of compound (1) 5 mg/kg and palbociclib 100 mg/kg as single agents versus the combination at each day.
    Tumor volume changes from baseline mm3: Median (nMAD)*, n and p-value#
    Treatment Group Global Day 27 Day 30 Day 34 Day 37 Day 41 Day 44 Day 49 Day 51
    Compound (1) 5 mg/kg + Palbociclib 100 mg/kg - -8.0 (63.75) n=9 -17.0 (97.85) n=9 -35.0 (74.13) n=9 -30.0 (57.82) n=9 -43.0 (60.79) n=9 -63.0 (45.96) n=9 -53.0 (72.65) n=9 -52.0 (72.65) n=9
    Palbociclib 100 mg/kg - 68.5 (31.88) n=10 98.0 (25.20) n=10 121.5 (34.10) n=10 132.0 (31.88) n=10 193.5 (52.63) n=10 249.5 (43.74) n=10 298.5 (97.11) n=10 363.5 (108.23) n=10
    <0.0001 0.2417 0.0736 0.0026 0.0002 <0.0001 <0.0001 <0.0001 <0.0001
    Compound (1) 5 mg/kg - 114.0 (19.27) n=8 171.5 (31.13) n=8 270.5 (112.68) n=8 336.0 (112.68) n=8 440.0 (39.29) n=8 498.5 (91.18) n=8 727.5 (160.86) n=8 782.0 (112.68) n=8
    <0.0001 0.0342 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001 <0.0001
    # p-values obtained with a contrast analysis to compare the combinations of compound (1) and palbociclib versus each single agent at the dose involved in the combination at each day with Bonferroni-Holm adjustment for multiplicity after a two-way Anova-Type on tumor volume changes from baseline.
    * MAD= Median Absolute Deviation; nMAD= normalized MAD ; nMAD= 1.4826*MAD
    The effect of the combination of compound (1) at 5 mg/kg + palbociclib at 100 mg/kg is significantly greater than the effect of palbociclib at 100 mg/kg alone on day 34 to day 51.
    The effect of the combination of compound (1) at 5 mg/kg + palbociclib at 100 mg/kg is significantly greater than the effect of compound (1) at 5 mg/kg alone on day 27 to day 51.
    n = number of animals. 3 mice were excluded from statistical analysis because those mice corresponded to non-drug related death or terminations during the study.

Claims (7)

  1. A combination comprising 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid, or a pharmaceutically acceptable salt thereof, with palbociclib.
  2. The combination according to claim 1, showing therapeutic synergy.
  3. The combination according to claim 1 or claim 2, for use in the treatment of cancer.
  4. The combination according to claim 4, wherein the cancer is breast cancer.
  5. A pharmaceutical composition comprising 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid, or a pharmaceutically acceptable salt thereof, and palbociclib, as well as at least one pharmaceutically acceptable excipient.
  6. The pharmaceutical composition according to claim 5, wherein 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid, or a pharmaceutically acceptable salt thereof, and palbociclib are administered simultaneously, separately, or spaced out over a period of time.
  7. A pharmaceutical kit which comprising:
    (i) a first pharmaceutical composition comprising 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7]annulene-2-carboxylic acid, or a pharmaceutically acceptable salt thereof, as well as at least one pharmaceutically acceptable excipient;
    (ii) a second pharmaceutical composition comprising palbociclib, as well as at least one pharmaceutically acceptable excipient;
    both pharmaceutical compositions (i) and (ii) being in separate compartments and being intended to be independently administered, each administration with regards to the other one being simultaneous, separated or spread out over time.
EP17305998.1A 2017-07-24 2017-07-25 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid Ceased EP3434272A1 (en)

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EP17305998.1A EP3434272A1 (en) 2017-07-25 2017-07-25 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid
SI201830528T SI3658147T1 (en) 2017-07-24 2018-07-23 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-(4-((3s)-1-(3-fluoropropyl)pyrrolidin-3-yl)oxyphenyl)-8,9-dihydro-7h-benzo(7)annulene-2-carboxylic acid and its use for the treatment of cancer
IL272166A IL272166B2 (en) 2017-07-24 2018-07-23 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid and its use for the treatment of cancer
MA49673A MA49673B1 (en) 2017-07-25 2018-07-23 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo [7]annulene-2-carboxylic acid and its use for the treatment of cancer
CN201880048755.5A CN111107851B (en) 2017-07-24 2018-07-23 Combination and use thereof for the treatment of cancer
AU2018308871A AU2018308871A1 (en) 2017-07-24 2018-07-23 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7] annulene-2-carboxylic acid and its use for the treatment of cancer
US16/634,089 US11260057B2 (en) 2017-07-24 2018-07-23 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[7] annulene-2-carboxylic acid and its use for the treatment of cancer
BR112020001398-6A BR112020001398A2 (en) 2017-07-24 2018-07-23 combination comprising palbociclib and 6-2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h- benzo[7]annulene-2-carboxylic acid and its use for cancer treatment
PL18740615T PL3658147T3 (en) 2017-07-24 2018-07-23 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid and its use for the treatment of cancer
PT187406152T PT3658147T (en) 2017-07-25 2018-07-23 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid and its use for the treatment of cancer
RU2020107416A RU2764116C2 (en) 2017-07-24 2018-07-23 Combination containing palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidine-3-yl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid and application thereof for treating cancer
CA3070754A CA3070754A1 (en) 2017-07-24 2018-07-23 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7] annulene-2-carboxylic acid and its use for the treatment of cancer
LTEPPCT/EP2018/069901T LT3658147T (en) 2017-07-24 2018-07-23 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid and its use for the treatment of cancer
HUE18740615A HUE057271T2 (en) 2017-07-24 2018-07-23 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid and its use for the treatment of cancer
RS20220068A RS62837B1 (en) 2017-07-24 2018-07-23 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid and its use for the treatment of cancer
DK18740615.2T DK3658147T3 (en) 2017-07-24 2018-07-23 COMBINATION INCLUDING PALBOCICLIB AND 6- (2,4-DICHLOROPHENYL) -5- [4 - [(3S) -1- (3-FLUOROPROPYL) PYRROLIDIN-3-YL] OXYPHENYL] -8,9-DIHYDRO-7H- BENZO [7] ANNULENE-2-CARBOXYLIC ACID, AND ITS USE FOR CANCER TREATMENT
JP2020503737A JP6741897B1 (en) 2017-07-24 2018-07-23 Parvocyclib and 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H-benzo[ 7] A combination comprising annulene-2-carboxylic acid and its use for the treatment of cancer
SG11202000367RA SG11202000367RA (en) 2017-07-24 2018-07-23 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7] annulene-2-carboxylic acid and its use for the treatment of cancer
EP18740615.2A EP3658147B1 (en) 2017-07-24 2018-07-23 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid and its use for the treatment of cancer
HRP20212030TT HRP20212030T1 (en) 2017-07-24 2018-07-23 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid and its use for the treatment of cancer
KR1020207002003A KR20200031622A (en) 2017-07-24 2018-07-23 Palbociclib and 6- (2,4-dichlorophenyl) -5- [4-[(3S) -1- (3-fluoropropyl) pyrrolidin-3-yl] oxyphenyl] -8,9- Combination comprising dihydro-7H-benzo [7] annulene-2-carboxylic acid, and its use for the treatment of cancer
PCT/EP2018/069901 WO2019020559A1 (en) 2017-07-24 2018-07-23 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7] annulene-2-carboxylic acid and its use for the treatment of cancer
MYPI2020000179A MY195271A (en) 2017-07-24 2018-07-23 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7] annulene-2-carboxylic acid and its use for the treatment of cancer
ES18740615T ES2906279T3 (en) 2017-07-24 2018-07-23 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3S)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7H- Benzo[7]annulene-2-carboxylic acid and its use for cancer treatment
ARP180102058 AR112284A1 (en) 2017-07-24 2018-07-24 COMBINATION INCLUDING PALBOCICLIB AND ACID 6- (2,4-DICHLOROPHENIL) -5- [4 - [(3S) -1- (3-FLUOROPROPYL) PYRROLIDIN-3-IL] OXIPHENIL] -8,9-DIHIDRO-7H- BENZO [7] ANNULENE-2-CARBOXYL
UY0001037818A UY37818A (en) 2017-07-24 2018-07-24 COMBINATION INCLUDING PALBOCICLIB AND ACID 6- (2,4-DICLOROPHENIL) -5- [4 - [(3S) -1- (3-FLUOROPROPIL) PIRROLIDIN-3-IL] OXIFENIL] -8,9-DIHIDRO-7H- BENZO [7] ANULEN-2-CARBOXYL
TW107125442A TWI768087B (en) 2017-07-24 2018-07-24 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7]annulene-2-carboxylic acid
ZA2020/00145A ZA202000145B (en) 2017-07-24 2020-01-09 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7] annulene-2-carboxylic acid and its use for the treatment of cancer
PH12020500091A PH12020500091A1 (en) 2017-07-24 2020-01-10 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7] annulene-2-carboxylic acid and its use for the treatment of cancer
CONC2020/0000240A CO2020000240A2 (en) 2017-07-24 2020-01-13 Combination comprising palbociclib and 6- (2,4-dichlorophenyl) -5- [4 - [(3s) -1- (3-fluoropropyl) pyrrolidin-3-yl] oxyphenyl] -8,9-dihydro-7h- benzo [7] annulene-2-carboxylic
US17/579,187 US20220362248A1 (en) 2017-07-24 2022-01-19 Combination comprising palbociclib and 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo[7] annulene-2-carboxylic acid and its use for the treatment of cancer

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